1) Field of the Invention
The present invention relates to novel 4-anilino[3,2-c]quinoline derivatives, which are found to have the ability to inhibit the growth of a variety of tumor/cancer cells (particularly melanoma cell lines UACC-62 and UACC-257, and one of the renal cancer cell lines, i.e. UO-31), the preparation processes of these derivatives, and their uses in the manufacture of pharmaceutical compositions.
2) Description of the Related Art
Acridine derivatives, especially 9-anilinoacridines, have been extensively studied as potential chemotherapeutic agents due to their capability of intercalating DNA leading to the inhibition of mammalian topoisomerase II (Atwell, G. J. et. al., J. Med. Chem. 1972, 15, 611-615; Denny, W. A. et. al., J. Med. Chem. 1978, 21, 5-10; Denny, W. A. et. al., J. Med. Chem. 1982, 25, 276-315; Gamage, S. A. et. al., J. Med. Chem. 1994, 37, 1486-1494; Gamage, S. A. et. al., J. Med. Chem. 1997, 40, 2634-2642). In these published articles, 4xe2x80x2-(9-acridinylamino) methanesulfonyl-m-anisidine (amsacrine, m-AMSA) is reported to be specifically relevant and has become a useful clinical drug for the treatment of leukemia and lymphoma (Atwell, G. J. et. al., J. Med. Chem. 1972, 15, 611-615).
A tremendous amount of effort has been directed toward the design and preparation of new amsacrine analogues with the aim of developing new drug candidates with an improved broad spectrum of antitumor activity (Baguley, B. C. et. al., J. Med. Chem. 1981, 24, 520-525; Rewcastle, G. W. et. al., J. Med. Chem. 1986, 29, 472-477; Denny, W. A. et. al., J Med. Chem. 1987, 30, 658-663; Su, T. L. et. al., J. Med. Chem. 1995, 38, 3226; Stanslas, J. et. al., J. Med. Chem. 2000, 43, 1563-1572).
However, the above-mentioned studies focused only on the 9-anilinoacridine skeleton, with a wide variety of substituents on anilino- and/or acridine chromophore. No attempt has been carried out concerning the replacement of acridine with its isosteric 4-anilinofuro[3,2-c]quinoline ring which constitutes an important group of natural products (Moulis, C. et. al., Phytochemistry 1983, 22, 2095 Reisch, J. and Iding, M., Montash. Chem. 1989, 120, 363).
Therefore, in the first aspect of this invention, the present invention provides novel 4-anilino[3,2-c]quinoline derivatives of formula (I): 
wherein
R1 represents: H, halogen, OH, NO2, NH2, a C1-C4 alkyl group, or a C1-C4 alkoxy group;
R2 represents a group of the following formula: 
xe2x80x83wherein
two of R3, R4, and R5 are H, and the other is 
xe2x80x83wherein
X represents O, S, NH, or NOR, R in NOR being H or a C1-C4 alkyl group; and
R6 represents H or a C1-C4 alkyl group.
In the second aspect, the present invention provides a pharmaceutical composition which comprises the above-described derivative, in its free type or a pharmaceutically acceptable salt thereof, as an active ingredient in inhibiting the growth of tumor/cancer cells, especially melanoma and renal cancer cells.
In the third aspect, the present invention provides processes for preparing the above-described derivatives of formula (I), as well as their intermediate compounds.
In particular, the present invention provides processes for preparing a compound of formula (Ixe2x80x2): 
wherein
R1 represents: H, halogen, OH, NO2, NH2, a C1-C4 alkyl group, or a C1-C4 alkoxy group;
R2xe2x80x2 represents a group of the following formula: 
xe2x80x83wherein
two of R3xe2x80x2, R4xe2x80x2 and R5xe2x80x2 are H, and the other is 
xe2x80x83wherein R6 represents H or a C1-C4 alkyl group;
the process comprising the step of reacting a compound of formula (A): 
wherein
R1 is the same as that defined for formula (Ixe2x80x2); and
Y represents: Cl, Br, or I;
with a compound of formula (B): 
wherein
R3xe2x80x2, R4xe2x80x2 and R5xe2x80x2 are the same as those defined for formula (Ixe2x80x2).
The above and other objects, features and advantages of the present invention will become apparent with reference to the following detailed description of the preferred examples.
After a variety of studies, the Applicant discovered a novel 4-anilino [3,2-c]quinoline derivative: 
wherein
R1 represents: H, halogen, OH, NO2, NH2, a C1-C4 alkyl group, or a C1-C4 alkoxy group;
R2 represents a group of formula: 
xe2x80x83wherein
two of R3, R4, and R5 are H, and the other is 
xe2x80x83wherein
X represents O, S, NH, or NOR, R in NOR being H or a C1-C4 alkyl group; and
R6 represents H or a C1-C4 alkyl group.
Preferably, R1 is H.
Preferably, R6 is CH3.
In a preferred embodiment, R3 and R5 are H, and R4 is 
In a more preferred embodiment, R3 and R5 are H, and R4 is 
In still another preferred embodiment, R3 and R5 are H, and R4 is 
In yet another preferred embodiment, R3 and R5 are H, and R4 is 
In a further preferred embodiment, R3 and R5 are H, and R4 is 
wherein R is H or a C1-C4 alkyl group, and, more preferably, R is CH3.
In a preferred embodiment, R4 and R5 are H, and R3 is 
In a more preferred embodiment, R4 and R5 are H, and R3 is 
In still another preferred embodiment, R4 and R5 are H, and R3 is 
In yet another preferred embodiment, R4 and R5 are H, and R3 is 
In a further preferred embodiment, R4 and R5 are H, and R3 is 
wherein R is H or a C1-C4 alkyl group, and, more preferably, R is CH3.
In a preferred embodiment, R1, R2 and R3 are all H, and R4 is selected from the group consisting of: 
wherein R is H or a C1-C4 alkyl group.
Through in vitro antitumor activity assay, the compound of formula (I) according to the present invention has been found to exhibit inhibitory activities against the growth of a variety of tumor/cancer cells, especially melanoma and renal cancer cells. Therefore, the present invention also envisions the application of the compounds of formula (I) of this invention or the pharmaceutically acceptable salts thereof in the manufacture of antitumor or anticancer compositions.
Therefore, a pharmaceutical composition according to the present invention comprises a compound of formula (I) as described above or the pharmaceutically acceptable salts thereof, and optionally, a pharmaceutically acceptable carrier.
As used herein, the pharmaceutically acceptable salts include salts with inorganic acids, such as hydrochloride, hydrobromide, sulfate, and phosphate; those with organic acids, such as acetate, maleate, tartrate, methanesulfonate; and those with amino acids, such as arginine, aspartic acid and glutamic acid.
The compounds of the present invention may also be present as a hydrate or as a stereoisomer. Therefore, it is contemplated that these hydrates and stereoisomers fall within the technical concept of the present invention.
As stated above, the pharmaceutical composition according to this invention may additionally comprise a pharmaceutically acceptable carrier widely employed in the art for the manufacture of medicaments. For example, the pharmaceutically acceptable carrier can include one or more of the following reagents: solvents, disintegrating agents, binders, excipients, lubricants, absorption delaying agents and the like.
The pharmaceutical composition according to this invention may be administered parenterally or orally in a suitable pharmaceutical form. Suitable pharmaceutical forms include sterile aqueous solutions or dispersions, sterile powders, tablets, troches, pills, capsules, and the like. In addition, the active compounds of the present invention may be incorporated into sustained-release preparations and formulations. Optionally, the pharmaceutical composition according to this invention may be administered alone or in conjunction with an additional anticancer agent, such as Mitomycin, Adriamycin, Actinomycin, cis-platin and the like.
The novel compound of the present invention may be prepared according to the following reaction schemes and protocols.
According to this invention, there is provided a process for producing a compound of formula (Ixe2x80x2): 
wherein
R1 represents: H, halogen, OH, NO2, NH2, a C1-C4 alkyl group, or a C1-C4 alkoxy group;
R2xe2x80x2 represents a group of the following formula: 
xe2x80x83wherein
two of R3xe2x80x2, R4xe2x80x2 and R5xe2x80x2 are H, and the other is 
xe2x80x83wherein R6 represents H or a C1-C4 alkyl group;
the process comprising the step of: reacting a compound of formula (A): 
wherein
R1 is the same as that defined for formula (Ixe2x80x2); and
Y represents: Cl, Br, or I;
with a compound of formula (B): 
wherein
R3xe2x80x2, R4xe2x80x2 and R5xe2x80x2 are the same as those defined for formula (Ixe2x80x2).
Preferably, the compound of formula (A) is 
and this compound is formed from the reaction of 
and POCl3.
Optionally, 
may be reacted with POCl3 and PCL5, or with SOCl2 in the presence of DMF, to thereby produce 
Concerning the preparation of 
reference is made to, for example, the following prior methods: 
(see Tuppy, H. and Bohm, F., Monatsh. 1956, 87, 735-740) 
(see Grundon, M. F. et al. J. Chem. Soc. 1955, 4284-4290) 
(see Gronowits, S. et al. J. Hterocyclic Chem., 1990, 27, 1159-1160)
Preferably, the compound of formula (B) is o-, m-, or p-aminoacetophenone. The aminoacetophenone compound may be chemically modified according to the prior methods, so that the methyl group present thereon is extended to a larger alkyl group (Doud, et al. J. Am. Chem. Soc. 1958, 80, 2205-2210).
In a preferred embodiment, the compound of formula (B) is 
preferably 
In another preferred embodiment, the compound of formula (B) is 
preferably 
In a preferred embodiment, the resultant compound of formula (Ixe2x80x2) according to the present process is further treated with a compound of formula NH2OR, in which R is H or a C1-C4 alkyl group, such that the 
group in the 
group of the compound of formula (Ixe2x80x2) is chemically modified to a 
group, wherein R is H or a C1-C4 alkyl group.
The compound of formula NH2OR may be prepared, e.g. according to the following prior method: 
(see Kim, J. N. et al., Synth. Commun., 1992, 22, 1427-1432).
In another preferred embodiment, the resultant compound of formula (Ixe2x80x2) according to the present process is further treated with a Lawesson""s reagent or P2S5, such that the 
group in the 
group of the compound of formula (Ixe2x80x2) is chemically modified to a 
group.
The chemical name of the Lawesson""s reagent is 4-methoxyphenylthiophosphine, which has the following structural formula: 
The Lawesson""s reagent is a commercial product available from Robinson Brothers Limited and may be used according to the manufacturer""s recommendations as posted on the internet website.
In another preferred embodiment, the resultant compound of formula (Ixe2x80x2) according to the present process is further treated with benzyldimethylphosphinimide, such that the 
group in the 
group of the compound of formula (Ixe2x80x2) is chemically modified to a 
group.
Concerning the use of benzyldimethylphosphinimide in the above chemical modification, reference is made to Wannagat, U.; Muenstedt, R. Phosphorus Sulfur, 1987, 29, 233-238.
In another preferred embodiment, the resultant compound of formula (Ixe2x80x2) according to the present process is further treated with NH2OH to chemically modify the 
group in the 
group of the compound of formula (Ixe2x80x2) to a 
group, followed by a treatment with a C1-C4 alkyl halide, to thereby modify the 
group to a 
group, wherein R is a C1-C4 alkyl group.
In order to more clearly describe the present invention, the following demonstration uses 
as the starting material, and the novel 4-anilino[3,2-c]quinoline derivatives of the present invention may be produced according to the following synthesis scheme: 
First, the known compound 5H-furo[3,2-c]quinolin-4-one (compound 1) is reacted with POCl3 to produce 4-chlorofuro[3,2-c]quinoline (compound 2). Compound 2 is further reacted with 3-aminoacetophenone in a solution of EtOH-H2 (2:1) to yield 1-[3-chlorofuro[3,2-c]quinolin-4-ylamino]phenyl)ethanone (compound 3).
The resultant Compound 3 may be further reacted with hydroxylamine or O-methylhydroxylamine to yield 1-[3-(furo[3,2-c]quinolin-4-ylamino) phenyl]ethanone oxime (compound 4) or 1-[3-(furo[3,2-c]quinolin-4-ylamino) phenyl]ethanone O-methyloxime (compound 5), respectively.
The 3-aminoacetophenone suitable for use in the synthesis of the above compound 3 is commercially available from Japan TCI Tokyo Kasei Kogyo Co., Ltd. In addition to 3-aminoacetophenone, the p- and m-stereoisomers thereof may be used in the synthesis scheme described above.
The hydroxylamine hydrochloride suitable for use in the synthesis of the above compound 4 is a commercial product available from, e.g. England Lancater Synthesis Ltd.